Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors; identifying genetic risk and protective factors by candidate gene and whole genome SNP and sequencing analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via a study of twins and close siblings discordant for systemic autoimmune disease. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes or idiopathic inflammatory myopathies (IIM) are defined by chronic muscle inflammation and weakness and are associated with specific autoantibodies. The major forms of myositis are polymyositis, in which multiple muscles are affected by inflammation, and dermatomyositis, in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. We are studying both the adult (IIM) and juvenile (JIIM) forms of these diseases to understand possible differences in pathogenesis and risk factors. One area of investigation in which we have made recent advances involves identifying new genetic associations with juvenile and adult IIM. To accomplish this goal, we formed collaborations with many investigators around the world called the Myositis Genetic Consortium (MYOGEN). Using samples from MYOGEN, we performed a genome-wide association study (GWAS) of adult and juvenile myositis patients of European ancestry and controls. To identify genetic risk factors, we conducted GWAS of the major myositis phenotypes in adult dermatomyositis, juvenile dermatomyositis; polymyositis, and adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with controls. Single-nucleotide polymorphisms showing strong associations (P < 5 X 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. We are continuing these investigations using Immunochip and other approaches and assessing additional phenotypes.